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Enfortumab Vedotin Versus Chemotherapy for Advanced Urothelial Carcinoma - Expert Commentary

Patients with advanced urothelial carcinoma (UC) still have low 5-year survival rates. Most patients experience disease progression after treatment with chemotherapy or PD-1 inhibitors. Enfortumab vedotin (EV) is an antibody-drug conjugate that targets Nectin-4, a protein highly expressed in UC. A recent study by Rosenberg et al. reports long-term outcomes from EV-301, an open-label phase III trial for EV versus chemotherapy in previously treated patients with advanced UC.

608 patients were randomized into the EV arm (n = 301) or chemotherapy arm (n = 307). There were 444 deaths in the cohort by the final cut-off point, two years after the trial began among patients receiving EV, 94.7% discontinued treatment compared to 98.0% of chemotherapy patients. The most common reason for this was progressive disease. A small percentage of patients receiving chemotherapy later crossed over to the EV treatment group (6%). The median follow-up was 23.75 months. Risk of death was reduced by 30% in the EV arm versus chemotherapy (HR, 0.70; 95% CI, 0.58 to 0.85; p = 0.00015). The median overall survival (OS) duration was 12.91 (95% CI, 11.01-14.92) and 8.94 (95% CI, 8.25-10.25) for EV and chemotherapy, respectively. The risk of disease progression or death was reduced by 37% in the EV group (HR, 0.63; 95% CI, 0.53-0.76, p < 0.00001). Median progression-free survival (PFS) was 5.55 (95% CI, 5.32-6.28) and 3.71 (95% CI, 3.52-3.94) months for EV and chemotherapy, respectively. Overall response was higher in the EV arm than in the chemotherapy arm (41.32% versus 18.58%, p < 0.001). Disease control was present in 71.88% of patients in the EV group (95% CI, 66.30-76.99) and 53.38% of patients in the chemotherapy group (95% CI, 47.52-59.17; p < 0.001).

The median duration of treatment was 4.99 months in the EV group and 3.45 months in the chemotherapy group. The incidence of treatment-related adverse events (TRAEs) was similar across the EV and chemotherapy groups (93.9% versus 91.8%). Similarly, the incidence of grade 3 or higher TRAEs was 52.4% in the EV arm and 50.5% in the chemotherapy arm. Common grade 3 or higher TRAEs included decreased neutrophil and white blood cell count, anemia in the chemotherapy group, maculopapular rash, fatigue, and peripheral sensory neuropathy in the EV group. Notably, the following events were more common in the EV arm than the chemotherapy arm: skin reactions (44.9% versus 9.6%), hyperglycemia (6.8% versus 0.3%), and peripheral neuropathy (48.0% versus 31.6%). Among patients receiving EV, the time to onset of skin reactions was 0.43 months, the time to onset of hyperglycemia was 0.62 months, and the time to onset of peripheral neuropathy was 2.81 months.

Overall, EV prolongs survival in pre-treated patients with advanced UC. Management of patients receiving EV must include routine monitoring for the development of AEs. Understanding potential biomarkers of response, including expression of the target antigen, factors in the microenvironment, and mechanisms of response and resistance to the cytotoxic payload, will be necessary for selecting patients most likely to benefit from this antibody-drug conjugate. Furthermore, understanding the mechanisms of neurotoxicity will be critical for preventing this adverse event.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

Reference:

  1. Rosenberg JE, Powles T, Sonpavde GP, et al. EV-301 long- term outcomes: 24-month findings from the phase III trial of enfortumab vedotin vs chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023. doi:10.1016/j.annonc.2023.08.016.
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